There is an increasing need to develop innovative approaches for manipulating elements of the immune system to produce multivalent vaccines. The identification and characterization of epitopes of viral proteins that elicit a protective immune response remain as a central obstacle to the developement of a vaccine against-virus infection. The implementation of an effective vaccine will require information that define the structural features of these motifs, identification of viral specific CTLs and effective in vitro and in vivo model systems to test the efficacy and safety of candidate vaccine preparations. We have successfully designed strategies for the engineering of structured peptides that mimic antibody recognition sites, delineated the conformational features of immunogenic peptides, used novel chimeric and multivalent designs to activate all arms of the immune system and utilizes animal models to present these immunogenic peptides in constructs that are designed to overcome major histocompatibility (MHC) restriction in a genetically diverse outbred human population. We have and will continue to focus our research efforts on the human T-lymphotropic virus type 1 (HTLV-1), the causative agent of T cell- Leukemia/lymphoma for these studies. We have selected HTLV-1 B -cell antigenic sites and identified putative CTL epitopes from HTLV-1 env and tax proteins using MHC class l allele specific motifs. We propose to (1) assess the effectiveness of epitope syntheses of putative B cell epitopes and "promiscuous" T cell epitopes in mice and rabbits, (2) develop microsphere delivery vehicles with effective, non toxic adjuvants, (3) continue to synthesize and characterize various antigenic peptides with a high degree of molecular mimicry, to test the immunogenicity of engineered constructs in mice and rabbits for their ability to induce high affinity neutralizing antibodies specific for the native HTLV-1 proteins, (4) to test the ability of predicted and known CTL epitopes to elicit enhanced CTL responses in mice, and (5) evaluate the efficacy of peptide vaccines by incorporating multiple neutralizing B cell epitopes, "promiscuous" T cell epitopes and cytotoxic T cell epitopes into a single template construct to obtain a universal vaccine effective at prevention of HTLV-1 infection of rabbits. We have made substantial progress in each of the above specific aims. The proposed research project will provide structural detail of immunodominant motifs of the HTLV-1 env and tax proteins, and contribute new knowledge about the immune response against HTLV-1 infection that will form the basis of an effective vaccine against the virus infection.